Aneuploidy, the loss or gain of chromosomes, is the leading cause of pregnancy failure and birth defects in humans. In most cases, aneuploidy originates from chromosome segregation errors in the egg. Human studies strongly indicate that events in the fetal ovary contribute to chromosome segregation errors in the adult. Despite this, almost nothing is known about the factors that regulate fetal oogenesis. The studies proposed in this application will begin to elucidate the factors that control fetal oogenesis. Ultimately, the objective of these and future studies is to understand the causes of aneuploidy so that miscarriage and birth defects such as Down syndrome can be prevented. The studies in this application will test the hypothesis that estrogen signaling is imperative for the events of fetal oogenesis, and this signaling is mediated directly at the level of the germ cell by the estrogen receptor (ER). Recent studies in the Hunt laboratory have demonstrated that, in mice, the estrogenic compound bisphenol A (BPA) and mutation of a classical estrogen receptor disrupt events in the fetal ovary. The first aim will refine the time of BPA action, testing the hypothesis that BPA acts in the premeiotic germ cell to affect subsequent events of meiosis. To test this, mice will be exposed to BPA during narrow windows that target premeiotic and meiotic stages of fetal oogenesis and effects assessed by analyzing meiotic prophase cells. An in vitro gonad culture system will also be used to target more specific points of BPA exposure. The second aim will test the hypothesis that estrogen has a critical role in fetal oogenesis, acting directly t the germ cell via ER. This will be tested with a germ cell specific ER knockout mouse model. To investigate the role of ER further, ER agonists and antagonists will be tested using the in vitro gonad culture system. These studies will begin to elucidate the role of estrogen in fetal oogenesis, the factors that contribute to aneuploidy, and the risk that endocrine disrupting chemicals pose to human fertility. PUBLIC HEALTH RELEVANCE: In humans, the primary cause of pregnancy failure and birth defects is errors in chromosome segregation during the formation of haploid gametes. Our studies suggest that estrogen may play a critical, yet previously unsuspected, role in the events of fetal oogenesis that set the stage for chromosome segregation in the adult. These studies represent a first step in understanding the role of estrogen on oogenesis and the potential impact of exposure to estrogenic compounds on female reproduction.